PROJECT SUMMARY Influenza virus is an important human pathogen that can cause severe disease and death in humans. Highly pathogenic influenza viruses, such as H5N1, induce excessive host responses that are associated with the production of pro-inflammatory cytokines, the recruitment of innate immune cells, and a diminished adaptive immune response. Unfortunately, the host and viral proteins involved in this pathogenic response are largely unknown. Accordingly, elucidating the mechanisms that underlie the host response to influenza virus is critical and will provide a framework for the rational design of new therapeutics for the treatment of pathogenic influenza infection. Genetic variation of the host can significantly influence the outcome of infection. In humans, polymorphisms in interferon regulatory factor 7 (IRF7) and interferon-induced transmembrane protein 3 (IFITM3) cause a predisposition to severe influenza disease, highlighting their importance in the pathogenesis of influenza. To identify additional host factors that modulate influenza disease, we took advantage of the increased susceptibility of the A/J mouse strain to highly pathogenic H5N1 influenza virus. Using a series of C57BL/6 mice harboring individual chromosomes from the A/J strain, we identified a single chromosome that increased the observed susceptibility to highly pathogenic H5N1 influenza virus relative to control animals. The increased susceptibility in the parent consomic strain was associated with higher viral loads in the lungs as well as increased production of pro-inflammatory cytokines, which are hallmarks of a severe H5N1 infection in humans. This proposal is aimed at (1) identifying the host factor that modulates virus replication and increased lethality after H5N1 virus infection and (2) determining the mechanism by which the identified factor exacerbates the disease. Successful completion of the proposed studies will lead to the identification of a novel host factor associated with severe disease.